Emerging studies show that T cell exhaustion correlates well with increased expression levels of inhibitory receptors including Programmed cell death receptor 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) during chronic infections. Both inhibitory molecules play similar but non-redundant role in T cell exhaustion. Engagement of PD-1 and CTLA-4 by their ligands inhibits T cell proliferation, cytokine secretion, and attenuates immune responses. Blockade of PD-1 and CTLA-4 restores effector function of exhausted T cells. PD-1 and CTLA-4 could both recruit Src homology 2-containing tyrosine phosphatase 2 (SHP2) and inhibit activation of Akt. Nevertheless, PD-1 and CTLA-4 also target distinct signaling molecules to inhibit T cell function. In this review, we will discuss current understanding of PD-1 and CTLA-4 initiated signaling pathways, their regulatory roles in a variety of chronic viral infections, and their promising potential as targets to enhance T cell function for antiviral therapy.